Recent studies suggest that reparative cells which contribute to healing in the lung following injury also possess regenerative capacity. Although the biology of post-natal lung regeneration is not well understood, mechanical pre-stress appears to be an absolute requirement for tissue regeneration to occur. Emphysema, a disease characterized by tissue destruction, is a potential target for cell-based therapy. This disease is associated with: 1) loss of resident reparative cells;2) loss of the extracellular matrix that transmits pre-stress signaling;3) and loss of pre-stress itself, the very signal required to trigger regenerative responses. Although these factors represent obstacles to the development of regenerative therapeutic strategies for emphysema, preliminary studies in our lab show that modulation of mesenchymal and epithelial cell proliferation using members of the fibroblast growth factor family complexed to carrier molecules in a biocompatible polymer can promote expansion of parenchymal tissues. The polymer scaffold, an air containing foam with mechanical properties similar to healthy lung tissue, effectively transmits stress to reparative/progenitor cells to promote proliferation and remodeling. Studies proposed here will test the hypothesis that 1) therapeutic post-natal lung tissue growth in emphysema can be achieved by augmenting the lung's innate healing response using growth factors to direct endogenous reparative lung cells following a localized mild injury;and that 2) the magnitude of this response can be modulated by altering pre-stress using concomitant bronchoscopic lung volume reduction therapy to increase transpulmonary pressures. We intend to advance this approach, known as pneumografting, into human trials under a physician-sponsored Investigation New Drug Application.